ABSTRACT Heart failure with preserved ejection fraction (HFpEF) affects approximately 2.9 million patients in the United States. HFpEF is both a morbid and mortal disease. It has a 60-65% five-year mortality rate after hospitalization, which is worse than most cancers. Unfortunately, physicians cannot directly address the extremely high rates of morbidity and mortality, as currently there are no treatments that improve survival. There is a also a relative paucity of data on the utility of biomarkers in prognosis or treatment of this disease, especially in comparison with heart failure with reduced ejection fraction. Moreover, patients with HFpEF often have several co-morbid conditions, such as obesity, and renal dysfunction, which can affect standard heart failure biomarkers such as natriuretic peptides and their interpretation. Recent epidemiologic data from our group showed that a new biomarker, the ratio of specific lipids in the plasma, i.e., ceramide 24:0/ceramide 16:0 (C24:0/C16:0) predicted incident heart failure and all-cause mortality in >5,000 subjects in two community-based cohorts: the Framingham Offspring cohort and the Study for Health in Pomerania even after accounting for standard cardiovascular risk factors. Moreover, the plasma C24:0/C16:0 altered the c-statistic for prediction of all-cause mortality. Whether this novel biomarker also predicts all-cause mortality and other secondary events in patients with known HFpEF is, as yet, unknown. The specific genes involved in the expression and regulation of this new biomarker is also not known. This study will address these gaps. We have approval from the BioLINCC repository to use already available data and plasma and genetic samples from the TOPCAT clinical trial, which was performed in patients with HFpEF for the Aims listed below. We will utilize a unique, well-validated liquid chromatography-tandem mass spectrometry (LC/MS-MS) lipidomic assay, which was developed at our institution. In addition, we will incorporate novel statistical genomic methodology to achieve the following Aims: 1. To assess the utility of the plasma C24:0/C16:0 ceramide ratio for secondary risk prediction in patients with known HFpEF from the TOPCAT trial. All-cause mortality will be the primary endpoint. A combined endpoint of cardiovascular death, heart failure hospitalizations, aborted cardiac arrest, and myocardial infarction will be evaluated as a secondary endpoint and all occurrences of the individual components of the secondary outcome will also be evaluated. 2. To characterize the genetic contributions to the plasma C24:0/C16:0 ratio and risk of death in HFpEF and to determine the potential causal impact of this ratio using data and genetic samples from TOPCAT, as well as novel statistical genomic methods including Mendelian Randomization.